The apolipoprotein E (APOE) epsilon 4 allele is a common susceptibility gene for Alzheimer's dementia (AD), which is present in almost one-fourth of the population and accounts for many late-onset cases. AD is associated with characteristic and progressive declines in positron emission tomography (PET) measurements of cerebral glucose metabolism and magnetic resonance imaging (MRI) measurements of brain volume. We have begun to longitudinally assess the changes in brain function, brain structure, and behavior that precede the onset of cognitive impairment in persons with two copies, one copy, and no copies of the s4 allele. As proposed in this competing continuation grant application, we will continue to acquire PET, MRI, clinical, neuropsychological, and psycholinguistic measurements every two years in 30 epsilon 4 homozygotes, 50 epsilon 4 heterozygotes, and 80 epsilon 4 noncarriers, who were initially 47-68 years of age and cognitively normal, had a reported family history of AD, and were individually matched for gender, age, and educational level. We will also acquire PET, MRI, clinical, and neuropsychological measurements every two years in 20 epsilon 4 carriers and 20 epsilon 4 noncarriers from the Hispanic community who are initially 47-68 years of age and cognitively normal and are matched for primary language, reported family history of AD, gender, age, and educational level. Advanced image-analysis techniques will be used to further characterize and compare changes in brain function and structure in the s4 homozygotes, heterozygotes, and noncarriers; to determine the extent to which our findings can be generalized to the Hispanic community; and to determine the extent to which baseline measurements and longitudinal changes in s4 carriers predict subsequent rates of cognitive decline. This study provides a foundation for our investigation of the changes in brain function, brain structure and behavior associated with the course of AD, MCI, presymptomatic vulnerability to these disorders, and normal aging; and it provides a foundation for using brain imaging techniques to assist in the early detection, tracking, understanding, and diagnosis of AD and in the discovery of interventions to treat and prevent this disorder. If, as postulated, declining PET and MRI measurements in cognitively normal epsilon 4 carriers ultimately predict rates of conversion to mild cognitive impairment (MCI) and AD, this study could provide an efficient way to demonstrate the efficacy of primary prevention therapies.